The Neutrophil-to-Lymphocyte Ratio is Associated with the Requirement and the Duration of Invasive Mechanical Ventilation in Acute Respiratory Distress Syndrome Patients: A Retrospective Study

Background Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality and most ARDS patients require ventilatory support. Applying appropriate ventilation strategies based on patients' individual situations has a direct impact upon patients' outcome. The neutrophil-to-lymphocyte ratio (NLR) has been shown to predict the early requirement of invasive mechanical ventilation (IMV) in patients with coronavirus disease 2019 (COVID-19). Our study aimed to investigate the relationship between baseline NLR and IMV in ARDS. Methods A retrospective study was performed on patients who were diagnosed with ARDS using the Berlin definition and admitted to the First Affiliated Hospital of Soochow University from 2017 to 2022. Clinical data within 24 h after the ARDS diagnosis were collected from the medical record system. Based on the ventilation strategies during hospitalization, patients were divided into three groups and their clinical characteristics were compared. Furthermore, logistic regression analysis was used to screen the independent risk factors for IMV. STROBE checklist was used for this manuscript. Results 520 ARDS patients were included and the median NLR value in IMV group was significantly higher than that of other groups (P < 0.001). NLR was significantly associated with the requirement of IMV in ARDS patients (OR, 1.042; 95% CI, 1.025–1.060; P < 0.001), other independent risk factors included PaO2/FiO2, Hb, lactate, and use of vasoactive drugs (all P < 0.05). Moreover, we found that the duration of IMV was longer in patients with high NLR (8[IQR, 3–13], 10[IQR, 6–16], respectively, P=0.025). Conclusions Our results revealed that high baseline NLR level was significantly correlated with an increased risk of IMV in patients with ARDS. Furthermore, higher NLR was associated with prolonged duration of IMV in patients with ARDS.


Introduction
Acute respiratory distress syndrome (ARDS) is a sudden and fatal illness that makes it difficult to get enough oxygen [1], with a mortality rate ranging from 35% to 40% [2,3]. ARDS severity is classified by the oxygenation index (PaO 2 /FiO 2 ), as severe (PaO 2 /FiO 2 ratio ≤100 mmHg), moderate (PaO 2 / FiO 2 ratio of 101-200 mmHg), and mild (PaO 2 /FiO 2 ratio of 201-300 mmHg), with mortality being increased with greater ARDS severity [4,5]. Most ARDS patients require noninvasive ventilation (NIV) or invasive mechanical ventilation (IMV) to decrease work of breathing and restore gas exchange [6]. Ventilator management differed among the ARDS severity groups. NIV can be implemented outside the intensive care units (ICU) and appear to be effective and safe in mild-to-moderate hypoxemia (PaO 2 /FiO 2 >150 mmHg), but they can yield delayed intubation with increased mortality in a significant proportion of moderateto-severe hypoxemia (PaO 2 /FiO 2 ≤150 mmHg). IMV is commonly used in moderate-to-severe individuals [7]. However, patients receiving IMV often have an increased length of hospital stay and mortality [8]. erefore, strict physiological monitoring and appropriate ventilation strategies based on patients' individual situations are extremely necessary.
e neutrophil-to-lymphocyte ratio (NLR) is a novel marker of systemic inflammatory response and is defined as the absolute neutrophil count divided by the absolute lymphocyte count, with normal NLR values ranging from 0.78 to 3.53 in an adult, nongeriatric population in good health [9]. Increased NLR has been proven to be valuable in the prognosis of several types of cancers [10], inflammatory diseases [11], and cardiovascular diseases [12]. In addition, an interim analysis of an ongoing prospective study showed that NLR at admission can predict the early requirement of IMV in patients with coronavirus disease 2019 (COVID-19) [13]. To our knowledge, the relationship between NLR and ventilatory support in ARDS patients has not yet been evaluated. erefore, the purpose of the present study was to assess the performance of baseline NLR for ARDS patients and reveal the relationship between NLR level and the requirement and duration of IMV during hospitalization.

Study Design and Patient Population.
is retrospective cohort study was approved by the Clinical Research Ethics Committee of First Affiliated Hospital of Soochow University (Jiangsu, China). Between January 2017 and May 2022, 2617 patients were diagnosed with respiratory failure in the First Affiliated Hospital of Soochow University. e medical records of all patients were reviewed by two attending physicians in the Department of Critical Care Medicine and then 632 patients fulfilled the inclusion criteria based on the Berlin definition [5] of ARDS (new or worsening respiratory symptoms began within 1 week of a known clinical insult, bilateral opacities on chest X-ray, PaO 2 /FiO 2 less than 300 mmHg with positive end-expiratory pressure being more than 5 cmH 2 O, no clinical evidence of left atrial hypertension, and no other explanation for these findings). We excluded individuals who were with history of blood system diseases, were less than 18    Canadian Respiratory Journal with NIV; 185 patients without ventilatory support) were enrolled in our study ( Figure 1).  (Table S1).

Baseline Characteristics of Patients.
A total of 520 ARDS patients were included in our study and were divided into three groups according to the ventilation strategies used during hospitalization ( Figure 1). e baseline characteristics of the non-MV and IMV groups are displayed in Table 1. Compared with patients without MV, patients with IMV were more likely to be male (P � 0.012), had lower PaO 2 /FiO 2 ratio, higher NLR values, and higher SOFA scores (both P < 0.001). Laboratory parameters (hemoglobin, hematocrit, platelets, lactate, and blood urea nitrogen) had significant statistical differences among different groups. Within the first 24 h after ARDS diagnosis, the IMV group was more likely to use steroid (59.6% vs. 49.2%; P � 0.042) and vasoactive drugs (45.1% vs. 14.6%; P < 0.001). Furthermore, categories of ARDS, 28-day mortality, and hospital length of stay in the two groups were significantly different (P < 0.001, P � 0.001, P � 0.002, respectively). e characteristics of the NIV and IMV groups are summarized in Table 2. Patients in the IMV group had higher NLR values (P � 0.001), lower PaO 2 /FiO 2 ratio (126, IQR: 82.94-184.62 vs 139, IQR:100-193.68, P � 0.040), higher severity of ARDS, and higher SOFA scores (8, IQR: 6-10 vs 7, IQR: 6-9, P � 0.022) and were more likely to use vasoactive drugs (45.1% vs. 28.2%; P � 0.002) within 24 h after the ARDS diagnosis compared with NIV group. Furthermore, patients with IMV had higher 28-day mortality and longer hospital length of stay (P � 0.023, P � 0.013, respectively). Details about baseline characteristics of the non-IMV and IMV groups are shown in Supplementary Material Table S2.

Discussion
In the current study, we demonstrated that the baseline NLR after diagnosis of ARDS was independently associated with an increased risk of IMV; other independent risk factors included PaO 2 /FiO 2 ratio, Hb, lactate, and the use of vasoactive drugs. Additionally, higher NLR was associated with prolonged duration of IMV in patients with ARDS. ARDS is a sudden and fatal disease with an increasing incidence rate, ranging from 20% to 40% and associated with high mortality (ranging from 35% to 40%) [2,3], as dramatically highlighted by the ongoing COVID-19 pandemic [18,19]. e histologic characteristic of ARDS is widely considered to be "diffuse alveolar damage," which is initially driven by dysregulated inflammation response [20]. In the acute stage of ARDS, tiny blood vessels in the lung become leaky, causing protein-rich fluid to fill up the smallest air sacs in the lung (called alveoli), and this is followed by interstitial widening by oedema and then fibroblast infiltration in the subacute phase [21]. COVID-19-related ARDS also causes the typical ARDS pathological changes of diffuse alveolar damage in the lung [22,23]. As a result, the lung cannot effectively provide oxygen to the rest of the body and clear carbon dioxide, which means that many ARDS patients require ventilator support with NIV or IMV to help them breathe [1]. A study based on the Spanish National Hospital Discharge Database investigated the epidemiological trends in MV use in Spain from 2001 to 2015, which showed an increase in the utilization of NIV while the use of IMV has decreased, and patients who received IMV had a higher inhospital mortality than those who received NIV [24]. In ARDS, NIV has been shown to be capable of preventing endotracheal intubation in patients with mild-to-moderate hypoxemia (PaO 2 /FiO 2 >150 mmHg), which is effective and safe. However, for patients with moderateto-severe hypoxemia (PaO 2 /FiO 2 ≤150 mmHg), the role of NIV strategies remains unclear [7]. Clinical outcome improves when NIV successfully allows avoiding endotracheal intubation. However, if IMV is needed after a failing trial of NIV, mortality is increased [25]. Consequently, it is important for clinicians to tailor interventions based on patients' individual requirements that can reduce mortality in patients with ARDS. NLR is the ratio of neutrophil to lymphocyte count and is a simple combined index that can be easily used to evaluate a patient's inflammatory status [26]. A study including 413 active subjects showed that normal NLR value ranges from 0.78 to 3.53 in an adult, nongeriatric population in good health [9]. Furthermore, NLR is a relatively stable parameter that did not significantly change with age and gender [27].    As the result of apoptosis in lymphocytes and an increase in neutrophils, the increase in NLR reflects the balance between lymphocyte count and neutrophil count and may reflect the systemic immune status more comprehensively [28]. Neutrophils are positively associated with the severity of inflammation in ARDS; moreover, they are the first immune cells to be recruited to the site of inflammation after being stimulated by chemokines released from injured lung tissue [23]. Meanwhile, the literature showed that lymphocytes were essential in regulating the appropriate inflammatory response, and low circulating lymphocytes may perpetuate a harmful inflammatory status [29,30].
Previous studies have shown that increased baseline NLR was associated with poor clinical outcomes in a variety of diseases, such as solid tumors [10,31], cardiovascular diseases [12], and inflammation-related diseases. Recent studies also reported the relationship between increased NLR and clinical prognosis of ARDS. e conclusions of these studies  [28]. In addition, a previous study including 81 patients with COVID-19 revealed that NLR >9.8 could predict the overall requirement of IMV [34]. An interim analysis of an ongoing prospective study showed that NLR >4.6 were moderately good in predicting the early requirement of MV within 24 h in COVID-19 patients [13].
Based on the available studies, we supposed that elevated NLR values are associated with IMV in ARDS patients on the evidence of the correlation between NLR-related inflammation and ARDS disease severity.
In the present study, we found the mortality of ARDS patients was quite high, and patients who received IMV had higher 28-day mortality and longer hospital length of stay than those who received NIV or without ventilatory support; this is consistent with previous studies. Besides, patients who received IMV had higher NLR levels, higher severity of ARDS, higher SOFA scores, and lower PaO 2 /FiO 2 ratios and were more likely to use vasoactive drugs at the time of ARDS diagnosis. Furthermore, there were some significant differences in sex and laboratory parameters (hemoglobin, hematocrit, platelets, lactate, and blood urea nitrogen) compared with non-MV group. We also observed that NLR was a risk factor for requirement of IMV in ARDS independent of Hb, lactate, vasoactive drugs, and Berlin classification. By combining NLR with other independent risk factors, we found it could reach a better predicting effect than using others alone, as indicated by the ROC curve analysis ( Figure 2). Severity of ARDS is related to the severity of pulmonary impairment, and more severe ARDS needs a prolonged ventilation time. In our study, patients with high NLR in the IMV group had a higher severity of ARDS and longer duration of IMV. 28-day mortality was also increased compared to those in the low NLR group. e current study suggests that this combined inflammatory-related parameter may be useful for assessing the disease severity, which might be helpful in evaluating the distribution of respiratory equipment in ARDS patients and adjusting clinical treatments and nursing interventions.
ere are several limitations in our study. Firstly, this is a retrospective study that included a small number of Chinese patients. Secondly, intubation and initiation of MV care were decided by attending physicians, which may have subjectively impacted on the outcome.
irdly, NLR was calculated only once at 24 h after the ARDS diagnosis, so whether continuous monitoring NLR level could better predict the requirement and the duration of IMV in patients with ARDS remains unclear. Further studies, particularly prospective studies with greater sample sizes, are needed to reveal the clinical significance of elevated NLR level and the correlation between NLR and IMV in patients with ARDS.

Conclusions
Based on the results of this study, NLR was elevated in ARDS patients, especially those with IMV. We found that high baseline NLR level was significantly correlated with an increased risk of IMV in patients with ARDS. Furthermore, higher NLR was associated with prolonged duration of IMV. erefore, this combined inflammatory index can function as a potential parameter to help evaluate the severity of ARDS and predict the requirement and the duration of IMV in patients with ARDS.
Data Availability e datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

Consent
Written informed consent was waived due to the retrospective nature of the study. All patient information was recorded anonymously to ensure confidentiality.

Conflicts of Interest
e authors declare that there are no reported conflicts of interest.

Authors' Contributions
Lijuan Yang, Chang Gao, and Ying He contributed equally to this work.

Supplementary Materials
Table S1: STROBE Statement: checklist of items that should be included in reports of cohort studies. Table S2: clinical and demographic characteristics of the enrolled patients.